British Medical Journal

Efficacy and Safety of Paracetamol for

Spinal Pain and Osteoarthritis
Systematic Review and Meta-analysis of Randomised Placebo Controlled
Trials

Gustavo C Machado, Chris G Maher, Paulo H Ferreira, Marina B Pinheiro, Chung-Wei

Christine Lin, Richard O Day, Andrew J McLachlan, Manuela L Ferreira

Disclosures

BMJ

http://www.medscape.com/viewarticle/842912

Abstract and Introduction

Abstract

Objective. To investigate the efficacy and safety of paracetamol (acetaminophen) in the

management of spinal pain and osteoarthritis of the hip or knee.

Design. Systematic review and meta-analysis.

Data Sources. Medline, Embase, AMED, CINAHL, Web of Science, LILACS,

International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials
from inception to December 2014.

Eligibility Criteria for Selecting Studies. Randomised controlled trials comparing the
efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and
osteoarthritis of the hip or knee.

Data Extraction. Two independent reviewers extracted data on pain, disability, and quality
of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue
medication. Pain and disability scores were converted to a scale of 0 (no pain or disability)
to 100 (worst possible pain or disability). We calculated weighted mean differences or risk
ratios and 95% confidence intervals using a random effects model. The Cochrane
Collaboration's tool was used for assessing risk of bias, and the GRADE approach was used
to evaluate the quality of evidence and summarise conclusions.

Results. 12 reports (13 randomised trials) were included. There was "high quality"
evidence that paracetamol is ineffective for reducing pain intensity (weighted mean
difference -0.5, 95% confidence interval -2.9 to 1.9) and disability (0.4, -1.7 to 2.5) or
improving quality of life (0.4, -0.9 to 1.7) in the short term in people with low back pain.
For hip or knee osteoarthritis there was "high quality" evidence that paracetamol provides a
significant, although not clinically important, effect on pain (-3.7, -5.5 to -1.9) and
disability (-2.9, -4.9 to -0.9) in the short term. The number of patients reporting any adverse
event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7
to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar
in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and
use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. "High quality"
evidence showed that patients taking paracetamol are nearly four times more likely to have
abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this
effect is uncertain.

Conclusions. Paracetamol is ineffective in the treatment of low back pain and provides
minimal short term benefit for people with osteoarthritis. These results support the
reconsideration of recommendations to use paracetamol for patients with low back pain and
osteoarthritis of the hip or knee in clinical practice guidelines.

Systematic Review Registration. PROSPERO registration number CRD42013006367.

Introduction

Low back and neck pain (spinal pain) are leading causes of disability worldwide, and
osteoarthritis of the hip or knee is the 11th highest contributor to global disability, when
disability is measured by years lived with disability.[1] The point prevalence of spinal pain
is 9.4%, and osteoarthritis affects nearly 4% of the global population.[2-4] The increasing
healthcare expenditure for these conditions is mostly attributed to the increasing cost of
prescription medicines, accounting for about 20% of the total cost.[5]

Prescription of drugs is the most common approach to treatment used by general

practitioners for spinal pain and osteoarthritis,[6] and guidelines consistently recommend the
prescription of paracetamol (acetaminophen) as the first line analgesic for these
conditions.[7-11] There has, however, been controversy about keeping paracetamol in the
most recent guidance on osteoar-thritis from the National Institute for Health and Care
Excellence,[12] mainly because of previous studies reporting small effects of paracetamol
compared with placebo.[13-15] Moreover, optimal therapeutic benefits of paracetamol might
require regular doses of up to 4000 mg/day.[16] There are some concerns regarding safety of
the full recommended dose,[17,18] although the evidence on safety is still debatable.[19]
Potential adverse effects and treatment schedule seem to also have a considerable effect on
patient adherence[20] as taking analgesics constantly and regularly three or four times a day
is inconvenient at least.

New randomised controlled trials[15,21] have been conducted since the last meta-analyses of
paracetamol for spinal pain and osteoarthritis of the hip or knee were published. There is
still uncertainty, however, whether consideration of new data changes the conclusions
regarding the efficacy and safety of paracetamol for these conditions. In this systematic
review we investigated the efficacy and safety of paracetamol in patients with spinal pain or
osteoarthritis of the hip or knee by including data from placebo controlled trials only, as
these represent the highest standard of evidence to inform the optimal use of drugs.[22]

Methods

Data Sources and Searches

We conducted a systematic review following the PRISMA statement[23] and prospectively

registered the review on PROSPERO. We carried out a systematic electronic search in
Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International
Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from
inception to 8 December 2014. We used a combination of relevant keywords to construct
the search strategy including paracetamol, acetaminophen, back pain, neck pain,
osteoarthritis, osteoarthro-sis, placebo, randomised, and controlled trial (see Appendix 1).
One author (GCM) conducted the first screening of potentially relevant records based on
titles and abstract, and two authors (GCM and MBP) independently performed the final
selection of included trials based on full text evaluation. Citation tracking was also
performed on included studies and relevant systematic reviews, and relevant websites and
clinical trials registries were searched for unpublished studies. Consensus between the two
reviewers was used to resolve any disagreement.

Study Selection

We included only randomised controlled trials comparing the efficacy of paracetamol

versus placebo. To be eligible, trials had to include participants with nonspecific spinal pain
(neck or low back pain) or osteoar-thritis of the hip or knee. We did not exclude trials in
mixed populations of patients with spinal pain and osteoarthritis. The intensity and duration
of symptoms were not restricted. There were also no restrictions for languages or
publication date. Studies that included patients with a serious spinal pathology (such as
cauda equina syndrome, tumour, or infection) were excluded. Studies with mixed
populations of patients with rheumatoid arthritis and osteoarthritis were also excluded,
unless separate data were reported for osteo-arthritis. Studies in which participants had
previous spinal, hip, or knee surgery remained eligible, but trials evaluating analgesia in the
immediate postoperative period were not included. We included only full reports in this
systematic review (that is, no abstracts).
Trials were eligible for inclusion when they reported at least one of the following primary
outcome measures: pain intensity, disability status, and quality of life. Secondary outcome
measures were safety (adverse effects), patient adherence, and use of rescue medication.

Data Extraction and Quality Assessment

Using a standardised data extraction form, two reviewers (GCM and MBP) independently
extracted study characteristics (details of participants, interventions, and outcomes) from
the included trials, and a third author (MLF) resolved any disagreement. We extracted
means, standard deviations, and sample sizes for our primary outcome measures. Mean
estimates were extracted in the following hierarchical order: mean differences, change
scores, and final values. For our secondary outcomes, we extracted the number of cases and
the total sample size. The safety outcomes extracted from included trials were the number
of patients reporting any adverse event, the number of patients reporting any serious
adverse event (as defined by each study), the number of patients withdrawn from study
because of adverse events, and the number of patients with abnormal results on liver
function tests (hepatic enzyme activity >1.5 times the upper limit of the reference range).
We contacted authors to provide further information when there were insufficient data
reported in the paper. When authors were unavailable we estimated data using the
recommendations in the Cochrane Handbook for Systematic Reviews of Interventions.[24]

Two reviewers (GCM and MBP) independently assessed the risk of bias of the included
studies using the Cochrane Collaboration's tool.[24,25] Consensus was used to resolve any
disagreement. RevMan version 5.3.5 was used to generate figures and summaries. The
quality of evidence was rated for each pooled analysis with the GRADE (grading of
recommendations assessment, development and evaluation) system,[26] with outcomes of
interest being ranked according to their relevance for clinical decision making as of limited
importance, important, or critical.[27] The quality of evidence was downgraded by one level
according to the following criteria: limitation of study design, inconsistency of results,
imprecision, and publication bias. We did not consider the indirectness criterion in this
review because we included a specific population with relevant outcomes and direct
comparisons.[28] Briefly, GRADE was downgraded by one level for limitation of study
design when more than a quarter of the studies included in an analysis were considered at
high risk of bias (that is, one or more bias domains were judged as high risk) according to
the Cochrane Handbook and thus plausible to affect the interpretation of our results.[24, 29]
Results were considered inconsistent if there was a wide variance of point estimates across
studies or if the heterogeneity between trials was large (I2>50%).[30] Imprecision was
identified when the upper or lower limits of the 95% confidence interval crossed the
minimal clinically important difference of 9 points (range 0-100).[31,32] We visually judged
a funnel plot (scatterplot of the effect of estimates from individual studies against its
standard error) and used Egger's test to investigate publication bias (small study effects).[33]
We included a total of 11 trials in the assessment of small study effects (nine trials
including patients with osteoarthritis and two trials including patients with back pain,
reporting data on immediate or short term pain intensity). If the Egger's test result was
significant (two tailed P<0.1) we would downgrade the quality of evidence (GRADE) by
one level for all meta-analyses.[34] The quality of evidence was defined as "high quality,"
"moderate quality," "low quality," and "very low quality."[26]

Data Synthesis and Analysis

We grouped the outcomes into four time points of assessment: immediate term (≤2 weeks),
short term (>2 weeks but ≤3 months), intermediate term (>3 months but ≤12 months), and
long term (>12 months). If studies reported multiple time points within each category, we
used the time point closest to one week for immediate term, eight weeks for short term, six
months for intermediate term, and 12 months for long term. When studies reported more
than one scale to measure pain we extracted the more severe estimate reported at baseline.
Scores for pain and disability were converted to a common 0 (no pain or disability) to 100
(worse pain or disability) scale. Pain intensity measures to calculate treatment effects were
numerical rating scale scores (range 0-10) or visual analogue scale scores (range 0-100).
These two pain measures are highly correlated and can be used interchangeably when
transformed.[35] Other measures of pain were also obtained from visual analogue scale
scores included in the Western Ontario and McMaster Universities osteoarthritis index
(WOMAC) pain subscale (VA3 series range 0-100)[36] and from the multi-dimensional
health assessment questionnaire (MDHAQ) pain subscale (range 0-100).[37] Disability
measures in the meta-analyses were WOMAC function subscale or WOMAC total
scores.[38] One study reported pain and disability measures from the WOMAC Likert
version (LK series), and the scores were also normalised to a scale of 0 to 100.

To facilitate the interpretation of our pooled estimates, we defined the effects of

paracetamol compared with placebo as ineffective when the 95% confidence interval
crossed the no effect line, showing no significant difference between groups. We
considered the minimal clinically important difference as a difference of 9 mm in a 0-100
mm visual analogue scale. This estimate has been used in past systematic reviews [32] to
investigate the efficacy of medicines compared with placebo for osteoarthritis and
corresponds to the median minimal clinically important difference found in trials
investigating patients with osteoarthritis. When our treatment effects were smaller than 9
mm, although significant, we considered the effect as small and not clinically important.

We used the I2 statistic to assess heterogeneity between trials, and values higher than 50%
were defined to identify high heterogeneity.[39] We calculated weighted mean differences or
risk ratios and 95% confidence intervals and used the random effects model to pool
estimates for each analysis obtained with Comprehensive Meta-Analysis version 2.2.064
(Englewood, NJ, 011).

Secondary Exploratory Analysis

We performed sensitivity analyses to explore the influence of each risk of bias domain on
pooled treatment effects. These stratified analyses were accompanied by meta-regression to
generate a P value for interaction between the bias domain and estimate of treatment effect.
For these analyses we used data from all osteoarthritis trials included in the meta-analysis
on short term pain (seven trials). As a previous study reported that small trials in
osteoarthritis tend to report more beneficial treatment effects than large trials,[40] we also
conducted a sensitivity analysis between large trials (sample size >100 per group) versus
small trials (sample size ≤100 per group) for all trials investigating patients with
osteoarthritis at immediate or short term follow-up. Negative differences in treatment
effects indicate that small trials have more beneficial effects than large trials.

Post Hoc Analysis

We carried out a post hoc analysis to assess the potential impact of a new trial on the
current evidence and thus to determine if a further new trial is justified. We used extended
funnel plots (graphical augmentations of the funnel plots commonly used to investigate
publication bias in meta-analyses)[41] to assess the impact of a new trial in our meta-
analysis. The extended funnel plots provide shaded contours that represent the contribution
of a new trial to existing evidence based on statistical simulations.[42] Addition of data from
a new trial of a certain sample size and treatment effect could result in the new conclusion
that the effect of intervention is clearly worthwhile or clearly not worthwhile, for instance.
We conducted extended funnel plots to assess the impact a further trial of paracetamol for
spinal pain and hip or knee osteoarthritis would have on the current evidence presented in
this meta-analysis. Stata 13 (StataCorp, College Station, TX) was used for this analysis.

Results

Our search results yielded 5498 records, and after excluding duplicates we screened 4037
titles and abstracts. Two independent reviewers evaluated 116 potentially relevant studies,
and 12 records (13 randomised controlled trials) met the criteria to be included in this
review, with one article reporting results of two trials (Fig 1).[43-54] Ten trials reporting data
from 3541 patients evaluated the efficacy of paracetamol in patients with osteoarthritis of
the hip or knee,[43,44,46-51,54] and three trials (1825 patients) investigated the efficacy of
paracetamol in people with low back pain.[45,52,53] We did not identify any trials in patients
with neck pain. Overall, the included trials assessed 5366 patients. We identified two
randomised trials published as abstracts and excluded them from this review.[55,56] One
randomised trial investigating the efficacy of paracetamol for low back pain did not report
results for the placebo group, and attempts to access these data from the authors and the
company that funded the study were unsuccessful.[45] This trial was included in the review
but not in the meta-analysis.

Figure 1.

Flow Chart of Trials Investigating Efficacy of Paracetamol in Spinal Pain and

Osteoarthritis. Numbers of records from each database include duplicates.
IPA=International Pharmaceuticals Abstracts, CENTRAL=Cochrane Register of Controlled
Trials

In the included studies paracetamol was primarily administered orally (as tablets/capsules).
One trial, however, reported the use of intravenous paracetamol in participants with chronic
low back pain.[52] The total oral dose and dose regimens for paracetamol varied across
trials, with 10 trials using a total dose of 39004000 mg/day and three trials using 3000
mg/day ( Table 1 ). Two trials used a three arm design, one included a third group that
received paracetamol as required,[53] and another included a third group that received a
lower dose of paracetamol (650 mg, one tablet, three times/day, 1950 mg total).[50] All three
treatment groups were included in the meta-analyses following the recommendation in the
Cochrane Handbook for Systematic Reviews of Interventions.[24] The washout period
before treatment started varied across trials, ranging from one day to six months. The
washout periods were 12 weeks for corticosteroids,[51] six weeks for intra-articular
steroids,[43] and ranged from three days to two weeks for non-steroidal anti-inflam-
matories.[43,46-48] Patients stopped taking simple analgesics from one to 10 days.[43,46,48,52]
One trial reported that the washout for glucosamine drugs was six months,[51] and two trials
used "five half lives" to define this period.[50,54]

We included six trials that reported data from people with chronic pain,[44,48,49,51,52] and two
studies that included people with acute pain only.[45,53] The remaining studies did not report
the duration of pain or disability. Nine trials used the diagnosis of osteoarthritis based on
image evidence and clinical assessment,[43,46-51,54] whereas one trial based the diagnosis
solely on image evidence.[44] Two trials used a clear definition of low back pain,[52,53] and
one trial used a simple question to define patients ("do the muscles of your low back
hurt?").[45] Table 1 includes more detailed information on included trials.

Figure 2.

Risk of Bias Summary Showing Review Authors’ Judgments About Each Risk of Bias
Domain in Placebo Controlled Trials on Efficacy of Paracetamol for Spinal Pain and
Osteoarthritis. Randomised clinical trials are listed alphabetically by author name

Figure 2 summarises the assessment of risk of bias for individual trials. Twelve trials had at
least one domain judged as unclear risk of bias. Four trials had at least one domain
considered as high risk of bias, and only one trial had all bias domains judged as low risk of
bias. Most trials (nine) failed to report the method used to generate the sequence allocation,
though all reported being randomised studies. Three trials adopted an appropriate method
of concealment of allocation, and only one trial failed to report blinding of patients,
personnel, and outcome assessors. Eight trials were funded by companies that produce
paracetamol and were considered as having unclear risk of bias for the other sources of bias
domain. As only one study reported data for intermediate term follow-up, its results were
pooled with trials reporting data for short term follow-up. None of the included trials
reported data for long term follow-up. The inspection of the funnel plot and the lack of
significance of the Egger's test (P=0.21) suggested no serious small study effects (see
Appendix 2, Fig A). We therefore considered that no meta-analysis presented serious
publication bias according to the GRADE approach. Figure 3 summarises pooled effect
sizes for pain and disability at immediate and short term follow-up. Table 2 and Table 3
present individual trial results and calculations of effect sizes. Figure 3.

Weighted Mean Differences for Pain and Disability in Placebo Controlled Trials on
Efficacy of Paracetamol for Spinal Pain and Hip or Knee Osteoarthritis. Pain and disability
are expressed on scale of 0-100. Immediate term=follow-up ≤2 weeks; short term=follow-
up evaluations >2 weeks but ≤3 months. Studies ordered chronologically within subgroups

Spinal Pain

Immediate Term Follow-up. Two trials including 1692 patients with low back pain tested
the effect of paracetamol compared with placebo in pain reduction.[52,53] Pooling showed no
effect of paracetamol on pain (weighted mean difference 1.4, 95% confidence interval -1.3
to 4.1; "moderate quality" evidence, downgraded for limitation of study design). For
disability, one trial evaluating 1652 patients found no difference between paracetamol and
placebo (-1.9, -4.8 to 1.0).[53] The quality of evidence for disability in the immediate term
was rated "high quality" according to the GRADE approach.

Short Term Follow-up. Only one trial investigated the short term efficacy of paracetamol
in 1652 patients with low back pain.[53] This trial showed no effect of paracetamol on pain
intensity (weighted mean difference -0.5, 95% confidence interval -2.9 to 1.9), disability
(0.4, -1.7 to 2.5), or quality of life measured by the 12-item short form health survey (SF-12
version 2) (0.4, -0.9 to 1.7) at short term follow-up. The quality of evidence (GRADE) for
all three outcomes was rated as "high quality." Table 4 and Table 5 summarise the findings
and quality assessment (GRADE) for outcomes ranked as critical for decision making.

Osteoarthritis

Immediate Term Follow-up. Five trials reported data from 1741 patients with hip or knee
osteoarthritis and were included in a meta-analysis to evaluate the immediate effect of
paracetamol in pain reduction.[44,46-48,54] Pooling showed that paracetamol has a small
benefit when compared with placebo in reducing pain (weighted mean difference -3.3, 95%
confidence interval -5.8 to -0.8; "high quality" evidence). For disability, pooling of three
trials with 1378 patients showed no immediate effect of paracetamol (-1.7, -6.0 to 2.6;
"moderate quality" evidence, downgraded for inconsistency).[46,48,54]

Short Term Follow-up. At short term follow-up, seven trials including 3153 patients with
hip or knee osteoarthritis were pooled to estimate the efficacy of paracetamol in reducing
pain and disability.[46,48-51,54] Pooling showed a significant small effect favouring
paracetamol for pain (weighted mean difference -3.7, 95% confidence interval -5.5 to -1.9).
Similarly, a significant but small benefit of paracetamol was found for short term reduction
in disability (-2.9, -4.9 to -0.9). The quality of evidence (GRADE) for both pooling was
rated as "high quality."

Secondary Outcomes

Our secondary outcomes included adverse effects, patient adherence, and use of rescue
medication. Fig 4 summarises the results.

Figure 4.

Risk Ratio for Safety Outcome Measures, Patient Adherence, and use of Rescue
Medication in Placebo Controlled Trials on Efficacy of Paracetamol Compared with
Placebo. Any=No of patients reporting any adverse event; serious=No of patients reporting
any serious adverse event (as defined by each study); withdrawals=No of patients
withdrawn from study because of adverse events; liver=No of patients with abnormal
results on liver function tests. Studies are ordered chronologically within subgroups

Adverse Effects. The type of adverse events reported by patients varied substantially
between trials. Nine trials investigated the number of participants reporting any adverse
event.[43,44,47-50,53,54] There was no difference in the number of patients reporting adverse
events between the paracetamol and placebo groups (risk ratio 1.0, 95% confidence interval
0.9 to 1.1; "moderate quality" evidence). The number of patients reporting any serious
adverse event (as defined by each study) was also similar in both paracetamol and placebo
groups (1.2, 0.7 to 2.1; "moderate quality" evidence).[48-51,53,54] Ten trials reported data on
the number of patients withdrawn from the study because of adverse events, with three of
these trials reporting no drop outs from adverse events. We found no significant difference
between groups for this outcome (1.2, 0.9 to 1.5; "high quality" evidence).[44,46,48-51] Three
trials evaluated the results of liver function tests to detect adverse effects of paracetamol
(activities of alanine aminotransferase, and/or aspartate aminotransferase) in participants
with osteoarthritis,[50,51,54] where an abnormal test was defined as hepatic enzyme activity
1.5 times the upper limit of the reference range or over. Pooling showed that participants
taking paracetamol are nearly four times more likely to have abnormal results on liver
function tests than participants taking placebo (3.8, 1.9 to 7.4; "high quality" evidence).

Patient Adherence. Two trials in patients with low back pain and osteoar-thritis
investigated adherence to study treatments, defined as the number of patients reporting
consumption of more than 70%[53] or 85%[48] of the recommended dose. We found no
difference in the number of participants adhering to study treatments between paracetamol
and placebo groups from the pooling of two trials (risk ratio 1.0, 95% confidence interval
0.9 to 1.1; "moderate quality" evidence, downgraded for inconsistency).

Use of Rescue Medication. This was measured as the number of patients using a rescue
medication (naproxen 250 mg, two tablets initially then one tablet every six to eight hours
as needed,[53] or ibuprofen 400 mg, one tablet every eight hours for a maximum of three
days[51]) during the trial. Pooled analysis of two trials in low back pain and osteoarthritis
showed no difference between the paracetamol and placebo groups (risk ratio 0.7, 95%
confidence interval 0.4 to 1.3; "high quality" evidence).

Secondary Exploratory Analysis

The results from our secondary analyses on the potential impact of individual risk of bias
domains on our treatment effects are presented in Fig B in Appendix 2. None of the
individual domains had a significant influence on the estimated treatment effect. Our
stratified analysis between small and large trials showed a difference of effects of 1.4 (95%
confidence interval -2.8 to 5.6), indicating that smaller trials tend to report less beneficial
effects, though this difference was not significant (P=0.51).

Extended Funnel Plot Assessment

After consideration of the results we carried out a post hoc analysis to assess the effect of a
new trial in our meta-analysis using extended funnel plots. Our results confirm that the
results of a new trial added to current evidence would not change the conclusion that
paracetamol does not deliver a clinically important benefit (at least 9 points out of a 0-100
range) for spinal pain and osteoarthritis (see Fig C in Appendix 2).

Discussion

There is "high quality" evidence that paracetamol has a significant but small effect in
patients with hip or knee osteoarthritis compared with placebo in the short term. The small
effects, <4 points on a 0-100 point scale, are not likely to be meaningful for clinicians or
patients. "High quality" evidence shows that paracetamol is ineffective for low back pain,
but we found no trials investigating neck pain. We also found "high quality" evidence that
paracetamol increases the risk of having an abnormal result on liver function tests by nearly
fourfold, although the impact of this on clinically relevant patient outcomes is unclear.
Adherence to the treatment protocol was similar in both paracetamol and placebo groups,
and there was also no difference in the use of rescue medication. Overall, our results are
based on "high quality" evidence (GRADE), and therefore further research is unlikely to
change this evidence. This systematic review should inform clinical practice and policy
with regard to first line care of these patients.

Strengths and Weaknesses of the Study

This systematic review was prospectively registered, and we followed the protocol
thoroughly. We included only placebo controlled trials in the review as they provide the
best evidence on the efficacy of pharmacological treatment.[22] We included 13 randomised
trials, 10 in people with hip or knee osteoarthritis, and three investigating people with low
back pain. We included two more trials than the last meta-analysis investigating people
with osteoarthritis,[15] and three more than the last review on people with spinal pain.[21] To
facilitate the interpretation of our results, we provide precise estimates and clinically
interpretable scores on 0-100 point scales of pain and disability. Overall, the quality of
evidence for our outcomes considered critical for clinical decision making was ranked
"high" according to the GRADE system. Moreover, this is the first review to report
evidence of changes in hepatic enzyme activity associated with paracetamol, patient
adherence, and use of rescue medication in patients with osteoarthritis and spinal pain.
Other strengths of our review included lack of restrictions to publication language or date
and use of hand search of clinical trial registries (for example, ClinicalTrials.gov) and
relevant websites for unpublished trials.

The number of studies in each meta-analysis was relatively small because of small number
of trials available on this topic (paracetamol versus placebo for spinal pain and
osteoarthritis). For instance, in the meta-analyses investigating the efficacy of paracetamol
on pain reduction for back pain we have included a maximum number of two trials, and for
osteoarthritis we included a maximum number of seven trials in a meta-analysis. Moreover,
none of the trials reported data for long term follow-up, and our results are limited to the
immediate and short term efficacy of paracetamol. Although we included three trials
investigating spinal pain, none of these trials included patients with neck pain. In addition,
one of the included trials did not report results for the placebo group,[45] and attempts to
gain access to these data were unsuccessful. Most of the included trials used the maximum
dose of 4000 mg/day recommended by the US Food and Drug Administration: seven trials
used 4000 mg/day as the maximum dose, two trials used 3990 mg as the maximum dose,
and two trials used 3900 mg as the maximum dose. Only two trials used 3000 mg/day as
the maximum dose.

Strengths and Weaknesses in Relation to Other Studies

Previous meta-analyses have concluded that paracetamol significantly reduces pain in

people with hip or knee osteoarthritis.[13-15] One of these reviews reported no difference in
toxicity, defined by the number of patients reporting any adverse event.[14] All endorsed the
use of paracetamol for pain reduction in such patients. Our review included two trials not
previously identified in the most recent previous meta-analysis, and our results show only a
small clinically irrelevant benefit of paracetamol for pain and disability at short term
follow-up.

Supratherapeutic doses of paracetamol can overwhelm the normal metabolic pathways and
protective mechanisms in the liver and produce dangerous amounts of a toxic metabolite,
N-acetyl-p-benzoqui-noneimine.[57] Most commonly this is seen in intentional overdoses,
and the consequence can be liver failure. However, the drug has been used extensively for
decades for chronic musculoskeletal conditions, and there is scant evidence for clinically
significant toxicity with regular doses of up to 4000 mg/day in otherwise healthy adults,
although some researchers contest this.[17] The significant effect on hepatic enzymes that
we show is well known,[58] but a link with clinically important toxicity is still uncertain.
Implications for Clinicians and Policymakers

Interventions such as drugs that aim to provide symptomatic relief have been associated
with improvement of physical function in people with osteoarthritis.[59,60] Similarly, there is
a high correlation of changes in pain scores and function scores in people with low back
pain.[61,62] This evidence supports the use of drugs for pain relief to improve function in
these conditions, and, overall, we have shown consistent results across pain and disability
outcome measures. We found that paracetamol is ineffective on both pain and disability
outcomes for low back pain in the immediate and short term and is not clinically superior to
placebo on both pain and disability outcomes for osteoarthritis.

Although thresholds for clinically important differences between groups are unknown for
osteoarthritis, a recent study has used a minimal clinically important difference of 0.9 on a
0-10 scale (or 9 on a 0 to 100 scale) based on the median difference found in previous large
trials including patients with osteoarthritis.[32] Our largest observed effect size of -3.7 points
on a 0-100 pain scale, favouring paracetamol, is unlikely to be considered clinically
important by patients or clinicians. Moreover, the lower boundary of the 95% confidence
interval of this effect size was -5.5 and still did not reach the minimal clinically important
difference of -9 defined in this review. Our results therefore provide an argument to
reconsider the endorsement of paracetamol in clinical practice guidelines for low back pain
and hip or knee osteoarthritis.

Recent evidence on lower limb osteoarthritis shows that exercises (such as strengthening
exercise) compared with no exercise control result in large treatment effects for pain
reduction (mean difference -2.3, 95% confidence interval -2.8 to -1.26; on a 10 cm visual
analogue scale).[63] This effect size is much larger than the largest effect size from our
pooled analyses on short term effects of paracetamol for hip or knee osteoarthritis.
Paracetamol alone therefore might not be sufficient to treat hip or knee osteoarthritis and
might need to be accompanied by other management strategies, such as exercises and
advice/education. Future trials, however, are needed to assess the combined effect of these
interventions in patients with osteoarthritis.

Unanswered Questions and Future Research

This systematic review shows precise and clinically interpretable estimates of the size of
the effect of paracetamol compared with placebo in the management of spinal pain and
osteoarthritis of the hip or knee. Although our results provide "high quality" evidence that
paracetamol does not provide a clinically important effect in the short term, the long term
effect of this drug in the treatment of spinal pain and osteoar-thritis remains unknown.
Moreover, we found higher risk of abnormal results on liver function tests in patients taking
paracetamol, though the clinical implications of this are uncertain. The effects of
paracetamol for neck pain are unknown as we found no trials including participants with
this condition.
British Medical Journal (April 2015)

Efikasi dan Keamanan Penggunaan Paracetamol untuk Nyeri Tulang

Belakang dan Osteoartritis
Review Sistematis dan Meta-analisis dari Randomised Placebo Controlled
Trials
Abstrak

Objektif
Menginvestigasi efikasi dan keamanan penggunaan paracetamol (acetaminophen) dalam
manajemen nyeri tulang belakang dan osteoartritis panggul/lutut.

Desain penelitian
Review sistematis dan meta analisis.

Sumber data
Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International
Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from
inception to December 2014.

Kriteria penelitian yang digunakan

Randomised controlled trials yang membandingkan efikasi dan keamanan penggunaan
paracetamol dengan plasebo pada nyeri tulang belakang (leher atau low back pain) dan
orteoartritis panggul/lutut.

Pengolahan data
Dua orang pengolah data independen mengekstraksi data berkaitan dengan nyeri,
disabilitas, dan kualitas hidup. Data sekunder lain menyangkut efek samping, kepatuhan
pasien, dan penggunaan obat darurat. Skoring nyeri dan disabilitas menggunakan skala 0
(tidak ada nyeri/disabilitas) sampai 100 (sangat nyeri/disabilitas). Untuk meminimalisir
bias, digunakan metode Cochrane Collaboration, dan untuk menyimpulkan hasil
digunakan GRADE approach.

Hasil
Penelitian yang digunakan sejumlah 12 studi. Terdapat bukti yang menunjukkan bahwa
paracetamol tidak efektif untuk mengurangi intensitas nyeri dan disabilitas, ataupun
meningkatkan kualitas hidup jangka pendek untuk pasien dengan low back pain. Untuk
osteoartritis panggul/lutut, paracetamol dapat mengurangi nyeri dan disabilitas secara
signifikan.
Jumlah pasien yang melaporkan efek samping obat ataupun mengundurkan diri dari
penelitian adalah sama baik dari plasebo maupun paracetamol, begitu juga dengan tingkat
kepatuhan pasien.
Terdapat hasil yang menunjukkan bahwa pasien yang mengonsumsi paracetamol hingga 4
kali sehari berisiko mengalami abnormalitas fungsi hati.

Kesimpulan
Paracetamol tidak efektif dalam menangani low back pain dan memberikan keuntungan
jangka pendek untuk pasien dengan osteoartritis.
Hasil ini mendukung evaluasi kembali dalam rekomendasi penggunaan paracetamol untuk
manajemen low back pain dan osteoartritis panggul/lutut.